Our previous grant (MH 274-23) examined primarily the electrical effects of imipramine on the heart. This proposal will examine the effect of imipramine on the mechanical performance of the heart. Our previous study revealed that at therapeutic antidepressant levels most of imipramine's effects on the heart were mild. The major adverse effects involved the potential for orthostatic hypotension and the apparent risk of extending heart block in patients with pre-existing conduction disease. This study will examine the mechanism of imipramine's orthostatic effect and will compare the risk of orthostatic hypotension and conduction defects with imipramine and nortriptyline. In order to examine these issues we plan to study two groups of depressed patients with pre-existing cardiovascular disease. In one group with pre-existing impaired left ventricular performance we will measure the effect of imipramine on performance by use of radioisotope angiocardiography. In this same group we will examine the mechanisms involved in orthostatic hypotension and will search for drug interactions with certain commonly used cardiovascular medications. In a second group of depressed patients with pre-existing conduction defects we will compare the propensity of imipramine and nortriptyline to produce orthostatic hypotension, and will establish and compare the risk of these two drugs extending pre-existing conduction defects. Plasma level measurements of the tricyclic drugs will be made by gas chromatography using a nitrogen detector. The information obtained in these studies will lead to a safer and more rational therapeutic use of antidepressant drugs and extend our basic understanding of the pharmacology of these compounds.